scholarly journals Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4285
Author(s):  
Viktorija Herceg ◽  
Jordan Bouilloux ◽  
Karolina Janikowska ◽  
Eric Allémann ◽  
Norbert Lange
Keyword(s):  
Cathepsin B ◽  
Cell Membrane Permeability ◽  
Cycle Arrest ◽  
Fibrosarcoma Cells ◽  
A Cell ◽  
Upper Face ◽  
G2 Phase ◽  
Human Fibrosarcoma Cells ◽  
Targeted Release

Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its toxicity, we used a Cathepsin B (Cat B)-sensitive prodrug concept for its targeted release since this enzyme is frequently overexpressed in cancer cells. Copper-free “click” chemistry was used to synthesize cPCPs containing up to four DOX moieties tethered to the upper face of the scaffold through a Cat B-cleavable peptidic linker (GAGRRAAG). On the lower part, PEG 5, 10 and 20 kDa and a fifth peptidyl DOX moiety were grafted in order to improve the solubility, bioavailability and pharmacokinetic profiles of the compound. In vitro results on HT1080 human fibrosarcoma cells showed that cPCPs display a delayed action that consists of a cell cycle arrest in the G2 phase comparable to DOX alone, and increased cell membrane permeability.

scholarly journals 4-Methylumbelliferone administration enhances radiosensitivity of human fibrosarcoma by intercellular communication

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryo Saga ◽  
Yusuke Matsuya ◽  
Rei Takahashi ◽  
Kazuki Hasegawa ◽  
Hiroyuki Date ◽  
...  
Keyword(s):  
Intercellular Communication ◽  
Dose Range ◽  
Synthesis Inhibitor ◽  
X Ray ◽  
Tumour Control ◽  
Synergetic Effects ◽  
Fibrosarcoma Cells ◽  
Oxidative Stress Level ◽  
Human Fibrosarcoma Cells

AbstractHyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) is a candidate of radiosensitizers which enables both anti-tumour and anti-metastasis effects in X-ray therapy. The curative effects under such 4-MU administration have been investigated in vitro; however, the radiosensitizing mechanisms remain unclear. Here, we investigated the radiosensitizing effects under 4-MU treatment from cell experiments and model estimations. We generated experimental surviving fractions of human fibrosarcoma cells (HT1080) after 4-MU treatment combined with X-ray irradiation. Meanwhilst, we also modelled the pharmacological effects of 4-MU treatment and theoretically analyzed the synergetic effects between 4-MU treatment and X-ray irradiation. The results show that the enhancement of cell killing by 4-MU treatment is the greatest in the intermediate dose range of around 4 Gy, which can be reproduced by considering intercellular communication (so called non-targeted effects) through the model analysis. As supposed to be the involvement of intercellular communication in radiosensitization, the oxidative stress level associated with reactive oxygen species (ROS), which leads to DNA damage induction, is significantly higher by the combination of 4-MU treatment and irradiation than only by X-ray irradiation, and the radiosensitization by 4-MU can be suppressed by the ROS inhibitors. These findings suggest that the synergetic effects between 4-MU treatment and irradiation are predominantly attributed to intercellular communication and provide more efficient tumour control than conventional X-ray therapy.

scholarly journals TNP-470 Suppresses the Tumorigenicity of HT1080 Fibrosarcoma Tumor Through the Inhibition of VEGF Secretion From the Tumor Cells

Sarcoma ◽  
2001 ◽  
Vol 5 (4) ◽  
pp. 197-202 ◽  
Author(s):  
Mitsunori Kaya ◽  
Takuro Wada ◽  
Satoshi Nagoya ◽  
Satoshi Kawaguchi ◽  
Toshihiko Yamashita ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Direct Action ◽  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
Fibrosarcoma Cells ◽  
Ht1080 Cells ◽  
Human Fibrosarcoma Cells ◽  
And Migration

Angiogenesis inhibitors are a novel class of promising therapeutic agents for treating cancer. TNP-470, a systemic analogue of fumagillin, is an angiogenesis inhibitor capable of suppressing the tumorigenicity in several animal models even though the mechanisms of action have not been completely clarified. In the current study, we investigated the effects of TNP-470 on human fibrosarcoma cellsin vivoandin vitro. The administration of TNP-470 could suppress the tumorigenicity of HT1080 fibrosarcoma tumor. The conditioned medium from HT1080 fibrosarcoma cells treated with TNP-470 inhibited the proliferation and migration of human endothelial cell line, HUVEC and ECV304. The concentration of VEGF in the conditioned medium from HT1080 cells treated with TNP-470 was lower than that of the cells without TNP-470 treatment, indicating that TNP-470 downregulates the secretion of VEGF from HT1080 cells. These findings strongly suggest that the direct action of TNP-470 on sarcoma cells inhibits angiogenesis through the downregulation of VEGF secretion and this angiogenesis suppression resulted in the inhibition of tumorigenicity of HT1080 fibrosarcoma tumo.

scholarly journals Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

2020 ◽  
Vol 8 ◽  
Author(s):  
Xiao Xue Ke ◽  
Rui Zhang ◽  
Xi Zhong ◽  
Lei Zhang ◽  
Hongjuan Cui
Keyword(s):  
Cell Proliferation ◽  
Cyclin B1 ◽  
Luciferase Reporter ◽  
Cycle Arrest ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
A Cell ◽  
Cell Proliferation Control

Glioblastoma is an aggressive and difficult to treat cancer. Recent data have emerged implicating that histone modification level may play a crucial role in glioma genesis. The histone lysine methyltransferase G9a is mainly responsible for the mono- and di-methylation of histone H3 lysine 9 (H3K9), whose overexpression is associated with a more aggressive phenotype in cancer. However, the detailed correlations between G9a and glioblastoma genesis remain to be further elucidated. Here, we show that G9a is essential for glioblastoma carcinogenesis and reveal a probable mechanism of it in cell proliferation control. We found that G9a was highly expressed in glioblastoma cells, and knockdown or inhibition of G9a significantly repressed cell proliferation and tumorigenesis ability both in vitro and in vivo. Besides, knockdown or inhibition of G9a led to a cell cycle arrest in G2 phase, as well as decreased the expression of CDK1, CDK2, Cyclin A2, and Cyclin B1, while it induced the activation of autophagy. Further investigation showed that G9a deficiency induced cell proliferation suppression, and activation of autophagy was rescued by overexpression of the full-length c-Myc. Chromatin immunoprecipitation (ChIP) assay showed that G9a was enriched on the −2267 to −1949 region of the c-Myc promoter in LN-229 cells and the −1949 to −1630 region of the c-Myc promoter in U-87 MG cells. Dual-luciferase reporter assay showed that c-Myc promoter activity was significantly reduced after knockdown or inhibition of G9a. Our study shows that G9a controls glioblastoma cell proliferation by transcriptionally modulating oncogene c-Myc and provides insight into the capabilities of G9a working as a potential therapeutic target in glioblastoma.

scholarly journals The Effect of Hydroxybenzoate Lithium Complexes in Inducing Apoptosis in HT-1080 Human Fibrosarcoma Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Jassem G. Mahdi ◽  
Eamon J. Mahdi ◽  
Amal Al-Hazzaa ◽  
Chris J. Pepper
Keyword(s):  
Biological Activities ◽  
Cytotoxic Activities ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Beneficial Effects ◽  
Fibrosarcoma Cells ◽  
Lithium Complexes ◽  
Human Fibrosarcoma Cells ◽  
Apoptotic Effects

There has been a growing interest in the beneficial effects of simple phenolic acids and their ability to exhibit various biological activities. The aim of this study was to assess in vitro biological activities of 2-, 3-, and 4-hydroxybenzoate lithium (HBLi) complexes on HT-1080 human fibrosarcoma cells by methods of using a metabolic activity assay, immunochemical and morphological techniques. Results showed that HBLi complexes exert their cytotoxic activities in a concentration- and chemical structure-dependent manner in the following order: 4-HBLi > 3-HBLi > 2-HBLi. Flow cytometry displayed evidence of apoptosis induced by 3-HBLi (21.8%) and 4-HBLi (33.2%). These results were verified by SEM, which revealed the formation of apoptotic bodies. In addition, these 3-HBLi and 4-HBLi caused an increase in HT-1080 cell cycle arrest in G0/G1 phase when compared to the controls (25% and 30.6%, resp.) when cells were treated with 6 mM for 24 hours. Immunochemical studies related to the molecular mechanism of apoptosis indicated that HBLi complexes downregulated the expression of Bcl-2 and upregulated Bax, p53, and caspases-3 in a concentration-dependent manner. HBLi complexes lowered Bcl-2/Bax ratios and induced the expression of p53 and caspase-3. These results suggest that HBLi complexes may exert their apoptotic effects through mitochondrial-mediated, caspase-dependent, apoptotic mechanisms.

Solvent-partitioned fractions from Ishige okamurae extract inhibit MMP-2 and MMP-9 activities in human fibrosarcoma cells in vitro

2017 ◽  
Vol 30 (1) ◽  
pp. 121-127
Author(s):  
Fatih Karadeniz ◽  
Seul-Gi Lee ◽  
Jung Hwan Oh ◽  
Ga Hyun Yu ◽  
Mi-Soon Jang ◽  
...  
Keyword(s):  
Ishige Okamurae ◽  
Fibrosarcoma Cells ◽  
Human Fibrosarcoma Cells

scholarly journals Reversal of Growth Suppression by p107 via Direct Phosphorylation by Cyclin D1/Cyclin-Dependent Kinase 4

2002 ◽  
Vol 22 (7) ◽  
pp. 2242-2254 ◽  
Author(s):  
Xiaohong Leng ◽  
Martin Noble ◽  
Peter D. Adams ◽  
Jun Qin ◽  
J. Wade Harper
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Control Cell ◽  
Growth Suppression ◽  
Cyclin Dependent Kinase ◽  
Culture Cells ◽  
Cycle Arrest ◽  
A Cell ◽  
Control Cell Division

ABSTRACT p107 functions to control cell division and development through interaction with members of the E2F family of transcription factors. p107 is phosphorylated in a cell cycle-regulated manner, and its phosphorylation leads to its release from E2F. Although it is known that p107 physically associates with E- and A-type cyclin/cyclin-dependent kinase 2 (Cdk2) complexes through a cyclin-binding RXL motif located in the spacer domain, the mechanisms underlying p107 inactivation via phosphorylation remain poorly defined. Recent genetic evidence indicates a requirement for cyclin D1/Cdk4 complexes in p107 inactivation. In this work, we provide direct biochemical evidence for the involvement of cyclin D1/Cdk4 in the inactivation of p107's growth-suppressive function. While coexpression of cyclin D1/Cdk4 can reverse the cell cycle arrest properties of p107 in Saos-2 cells, we find that p107 in which the Lys-Arg-Arg-Leu sequence of the RXL motif is replaced by four alanine residues is largely refractory to inactivation by cyclin D/Cdk4, indicating a role for this motif in p107 inactivation without a requirement for its tight interaction with cyclin D1/Cdk4. We identified four phosphorylation sites in p107 (Thr-369, Ser-640, Ser-964, and Ser-975) that are efficiently phosphorylated by Cdk4 but not by Cdk2 in vitro and are also phosphorylated in tissue culture cells. Growth suppression by p107 containing nonphosphorylatable residues in these four sites is not reversed by coexpression of cyclin D1/Cdk4. In model p107 spacer region peptides, phosphorylation of S640 by cyclin D1/Cdk4 is strictly dependent upon an intact RXL motif, but phosphorylation of this site in the absence of an RXL motif can be partially restored by replacement of S643 by arginine. This suggests that one role for the RXL motif is to facilitate phosphorylation of nonconsensus Cdk substrates. Taken together, these data indicate that p107 is inactivated by cyclin D1/Cdk4 via direct phosphorylation and that the RXL motif of p107 plays a role in its inactivation by Cdk4 in the absence of stable binding.

Effect of trna from 5-azacytidine-treated hamster fibrosarcoma cells on protein synthesis in vitro in a cell-free system

1976 ◽  
Vol 25 (4) ◽  
pp. 389-392 ◽  
Author(s):  
Richard L. Momparler ◽  
Stuart Siegel ◽  
Felicidad Avila ◽  
Thomas Lee ◽  
Myron Karon
Keyword(s):  
Protein Synthesis ◽  
Free System ◽  
Cell Free System ◽  
Fibrosarcoma Cells ◽  
A Cell ◽  
Hamster Fibrosarcoma

scholarly journals Stanniocalcin 1 and 2 are secreted as phosphoproteins from human fibrosarcoma cells

2000 ◽  
Vol 350 (2) ◽  
pp. 453-461 ◽  
Author(s):  
Derek A. JELLINEK ◽  
Andy C. CHANG ◽  
Martin R. LARSEN ◽  
Xin WANG ◽  
Phillip J. ROBINSON ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mammalian Cells ◽  
Phosphorylation Site ◽  
Mrna Levels ◽  
Intact Cells ◽  
Fibrosarcoma Cells ◽  
Ht1080 Cells ◽  
Human Fibrosarcoma Cells

Stanniocalcin 1 (STC1) and stanniocalcin 2 (STC2) are two recently identified mammalian peptide hormones. STC1 plays a role in calcium and phosphate homoeostasis, while the role of STC2 is unknown. We examined a human fibrosarcoma cell line, HT1080, that has high steady-state STC1 and STC2 mRNA levels, to determine whether these proteins are secreted. Following incubation of HT1080 cells with 32P, labelled STC1 and STC2 were found to be secreted into the medium. STC1 was phosphorylated in vitro by protein kinase C (PKC). In vitro and in vivo phosphorylation both occurred exclusively on serine and the phosphopeptide maps were similar, suggesting that PKC might be the in vivo kinase. STC2 was phosphorylated in vitro by casein kinase II (CK2), in vitro and in vivo phosphorylation were exclusively on serine and the phosphopeptide maps were indistinguishable. Phosphorylation of STC2 in intact cells resulted from the action of an ecto-protein kinase, since exogenous STC2 was phosphorylated by HT1080 cells and no phosphorylated STC2 was detectable inside the cells. The ectokinase activity was abolished by heparin and GTP could substitute for ATP as the phosphate donor, indicative of an ecto-CK2-like activity. The in vitro CK2 phosphorylation site was shown by matrix-assisted laser-desorption ionization–time-of-flight MS to be a single serine located between Ser-285 and Ser-298 in the C-terminal region of STC2. This is the first report of the secretion of STC1 or STC2 from mammalian cells. We conclude that these human fibrosarcoma cells express both STC1 and STC2 as secreted phosphoproteins in vivo, with STC2 being phosphorylated by an ecto-CK2-like enzyme.

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